2-mercaptobenzimidazole and Body-Weight

2-Mercaptobenzimidazole (MBI), a rubber antioxidant, is known to exhibit potent thyroid toxicity in rats, whereas its methylated derivatives are much less toxic. To characterize this methyl-substituent effect on the thyroid toxicity of MBI, comparative toxicokinetic analyses have been conducted in the present study. MBI and the MMBIs [4-methylated MBI (4-MMBI) and 5-methylated MBI (5-MMBI), and a 1:1 mixture of these 4- and 5-methylated isomers (MMBI mix)] suspended in corn oil were repeatedly administered (at 0.3-0.6 mmol/kg) to male Wistar rats by gavage once daily for 2 weeks. After the first and last administrations, blood and urine samples were collected, and the levels of unchanged compounds and their desulfurated metabolites were determined by high performance liquid chromatography. After repeated oral administration (roa), the C(max) and area under concentration-time curve (AUC) of MBI were markedly increased, while the MMBIs essentially were cleared from the blood within 10 h. After roa, the C(max) and AUC of 4-MMBI decreased markedly, suggesting metabolic enzyme induction. However, the toxicokinetic parameters of 5-MMBI were not markedly altered by roa. The inhibitory potencies (IC(50)) against lactoperoxidase of MBI, 4-MMBI, and 5-MMBI were 20.6 micro M, 45.6 micro M and 31.6 micro M, respectively. Thus, we suggest that the marked decrease of thyroid toxicity by methyl substitution of MBI is caused mainly by a decrease in systemic exposure to the compounds and partly by a decrease in inhibition of thyroid hormone synthesis.

Topics: Administration, Oral; Animals; Antioxidants; Area Under Curve; Benzimidazoles; Body Weight; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Combinations; Lactoperoxidase; Liver; Male; Organ Size; Rats; Rats, Wistar; Specific Pathogen-Free Organisms; Thyroid Gland

The chemical structure of 2-mercaptobenzimidazole (2-MBI), which is widely used as a rubber antioxidant, is partially similar to those of thiourea (TU) and ethylenethiourea (ETU), both potent thyrotoxic compounds. In order to determine the oral toxicity of 2-MBI, a 28-day repeated dose toxicity study in Wistar rats followed by observation over a 14-day recovery period was conducted at dose levels of 2, 10 and 50 mg/kg 2-MBI administered by gavage. No toxic deaths occurred due to 2-MBI treatment. Decreases of body weight gain and food consumption in the 50 mg/kg dose group were observed during the second half of the treatment period. In addition, hematological examination and serum biochemical tests revealed decreased white blood cells and hemoglobin and increased serum urea nitrogen, cholesterol, phospholipid, gamma-glutamyl transpeptidase and the Na+/K+ ratio in the 50 mg/kg dose group. Marked thyroid enlargement (to 10 fold the control weight), histopathologically associated with diffuse hyperplasia of follicles with decreased colloid and thickening of the fibrous capsule, was found. Reduction in thymus weight was also observed in a dose-dependent manner, without significant histopathological alteration. The non-observed effect level (NOEL) of 2-MBI in this gavage study was found to be less than 2 mg/kg/day based on the significant decrease in thymus weight in the 2 mg/kg 2-MBI treatment group. In an ancillary study, measurement of serum levels of T3, T4 and TSH, and thyroid weight after gavage treatment with 0.15 and 0.3 mmol/kg of three antithyroid compounds for 14 days revealed a more potent antithyroid effect for 2-MBI than for TU or ETU.

Topics: Administration, Oral; Animals; Antioxidants; Benzimidazoles; Blood Urea Nitrogen; Body Weight; Cholesterol; Eating; Female; gamma-Glutamyltransferase; Hemoglobins; Hyperplasia; Leukocyte Count; Male; Organ Size; Phospholipids; Potassium; Rats; Rats, Wistar; Rubber; Sodium; Thymus Gland; Thyroid Gland; Thyroid Hormones

The effects of oral 2-mercaptobenzimidazole (2-MBI) on pregnant Wistar rats were examined. In a preliminary dose-finding study, pregnant rats treated with 2-MBI over Days 7-17 of gestation showed reduction in maternal thymus weights with compound-related mortality at doses > or = 40 mg/kg. No adverse effects on fetuses were found at doses < or = 40 mg/kg. However, anasarca, cleft palate, and dilated lateral ventricles were present in all fetuses from the only survivor among the dams treated with 60 mg/kg of 2-MBI. In the teratology study, pregnant rats were treated with 2-MBI at doses of 0, 3.3, 10, and 30 mg/kg during the period of organogenesis (Gestation Days 7-17). In addition, pregnant rats of three groups were also treated with 60 mg/kg of 2-MBI for 3 or 4 days during specific periods of organogenesis (Days 7-10, 11-14, or 15-17 of gestation). Treatment on Gestation Days 7-17 resulted in reduced maternal thymus weights at doses of > or = 3.3 mg/kg. In addition to reduced fetal weights, visceral variations (kinked ureter and dilated renal pelvis) and delayed ossification were seen in the fetuses at doses > or = 10 mg/kg, and skeletal variations (rudimentary lumbar ribs) were seen at 30 mg/kg. In the fetuses from the dams treated with 60 mg/kg of 2-MBI, rudimentary lumbar ribs were seen mainly in the group treated on Days 7-10 of gestation, whereas kinked ureter and dilated renal pelvis were evident mainly in the group treated on Gestation Days 15-17.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Benzimidazoles; Body Weight; Bone and Bones; Brain; Cleft Palate; Eating; Embryonic and Fetal Development; Female; Kidney; Male; Pregnancy; Pregnancy, Animal; Rats; Ribs; Toxicity Tests; Ureter

2-Mercaptobenzimidazole (2-MBI), used in rubber processing, is a suspect carcinogen structurally related to ethylene thiourea. The inhalation toxicity of 2-MBI was evaluated in male and female F344/N rats exposed 6 hr/day, 5 days/week to respirable aerosols generated by spray atomization of aqueous suspensions of the 2-MBI powder and subsequent drying of the resulting aerosols. Twelve exposures at target concentrations of 0, 6.3, 12.5, 25.0, 50.0, or 100 mg/m3 of 2-MBI produced a dose-related reduction in body weight gains, thyroid follicular cell hyperplasia, adrenal cortex fatty change, and pituitary atrophy. Sub-chronic exposures were conducted at target concentrations of 0, 3.1, 6.2, 12.5, 25.0, and 50.0 mg/m3 of 2-MBI. Rats at greater than or equal to 25 mg/m3 displayed hunched posture, hypoactivity, and reduced body weight gain, with compound related mortality at the highest exposure level. Anemia; increased SGPT, SGOT, alkaline phosphatase, sorbitol dehydrogenase, BUN, and cholesterol; and reduced free fatty acid were seen in rats at greater than or equal to 25 mg/m3. Increased thyroid weight and thyroid follicular cell hyperplasia were noted in both sexes at greater than or equal to 6.2 mg/m3, with reduced triiodothyronine and thyroxine levels in both sexes at greater than or equal to 12.5 mg/m3. Thyroid follicular cell hyperplasia was also seen in rats at 3.1 mg/m3. Thymus weights were significantly reduced in both sexes at all exposure levels with liver weight increases at greater than or equal to 6.2 mg/m3. Exposure-related histopathologic changes included pituitary cytoplasmic vacuolization, adrenal cortex necrosis, lymphoid depletion, thymic atrophy, liver cell hypertrophy, renal mineralization and tubular atrophy, and hypocellularity of the bone marrow.

Topics: Administration, Inhalation; Aerosols; Animals; Antimetabolites; Benzimidazoles; Body Weight; Enzymes; Male; Organ Size; Particle Size; Radioimmunoassay; Rats; Rats, Inbred F344; Sex Factors; Thyroxine; Triiodothyronine